This project involves clinical research in obsessive-compulsive disorder (OCD) primarily directed towards (1) family and genetic studies of OCD and OCD "spectrum" disorders and related disorders, and (2) enhancement of our understanding of OCD pathogenesis.OCD is a severe, heritable condition with a lifetime prevalence of about two percent of the world population. The mode of inheritance is poorly understood but is likely complex, involving multiple loci of small to moderate effect. Our laboratory has been active in studies of OCD and its genetics for over 10 years, and last year became one of the founding sites of a multi-center genetic study of OCD, led by Dr. Gerald Nestadt of Johns Hopkins University. Our OCD genetic studies in the NIMH IRP contribute DNA and family evaluation data to this national multi-site, planned genome-wide study of OCD. Standardized diagnostic and other ascertainments are being used by all six sites within the OCD genetics consortium. It is anticipated that this consortium will add 300 new families with affected sib-pairs over the next three years. This sample will be used for linkage and association analyses. Genotypes will be shared within this consortium of investigators studying OCD and will eventually be combined with data obtained from a second U.S. consortium. In addition, exploratory analyses of DNA, clinical features and personality characteristics of OCD probands and of disorders related to OCD are being used to assess the candidacy status of gene variants and to better define the familial OCD phenotype. The NIMH-IRP OCD project has now enrolled and completely ascertained 344 individuals with OCD and family members (including 11 affected sibling pairs and their family members plus 25 trios evaluated this past year). Other families are in varying stages of completing the protocol requirements. An association between a 5-HT2A receptor promoter polymorphism in both our OCD sample and an anorexia nervosa sample, but not with a comparison group of patients with bulimia nervosa, was found to be sexually dimorphic, a characteristic of women, but not men with OCD. Continuation of this study will allow expansion of a sample of OCD probands, affected sibling pairs and their family members. This should add to the likelihood of identifying chromosomal regions and genes relevant to OCD and related neuropsychiatric disorders.